Biased signaling pathways via CXCR3 control the development and function of CD4+ T cell subsets

Abstract

Structurally related chemotactic cytokines (chemokines) regulate cell trafficking through interactions with 7-transmembrane domain, G protein-coupled receptors. Biased signaling or functional selectivity is a concept that describes a situation where a 7-transmembrane domain receptor preferentially activates one of several available cellular signaling pathways. It can be divided into 3 distinct cases: ligand bias, receptor bias, and tissue or cell bias. Many studies, including those coming from our lab, have shown that only a limited number of chemokines are key drivers of inflammation. We have referred to them as "driver chemokines." They include the CXCR3 ligands CXCL9 and CXCL10, the CCR2 ligand CCL2, all 3 CCR5 ligands, and the CCR9 ligand CCL25. As for CXCR3, despite the proinflammatory nature of CXCL10 and CXCL9, transgenic mice lacking CXCR3 display an aggravated manifestation of different autoimmune disease, including Type I diabetes and experimental autoimmune encephalomyelitis. Recently, we showed that whereas CXCL9 and CXCL10 induce effector Th1/Th17 cells to promote inflammation, CXCL11, with a relatively higher binding affinity to CXCR3, drives the development of the forkhead box P3-negative IL-10 high T regulatory 1 cell subset and hence, dampens inflammation. We also showed that CXCL9/CXCL10 activates a different signaling cascade than CXCL11, despite binding to the same receptor, CXCR3, which results in these diverse biologic activities. This provides new evidence for the role of biased signaling in regulating biologic activities, in which CXCL11 induces ligand bias at CXCR3 and receptor-biased signaling via atypical chemokine receptor 3.

ZNF395 Is an Activator of a Subset of IFN-Stimulated Genes

“…CXCL10 induces Th1/Th17 cells to promote inflammation. In contrast, CXCL11 binding to the CXCR3 results in the development of IL-10 high T regulatory 1 subsets, leading to dampening of inflammation [4]. Taken into account that CXCL11 has higher affinity to the CXCR3, our findings presented here are in line with the model that high level of ZNF395 elevates the amount of CXCL11 thus dampening inflammation while low ZNF395 level might mainly support inflammation via inducing CXCL10.…”

“…The three chemokines are ligands of the CXCR3 receptor that is expressed on different leucocyte subsets including monocytes, natural killer (NK) cells, and activated T lymphocytes and attract these leucocytes to local sites of inflammation [3]. Signaling induced by binding of these chemokines to the CXCR3 controls the development and function of CD4 + T cell subsets and thus contributes to the regulation of the inflammatory process [4]. The CXCR3 receptor and its ligands, specifically CXCL10 and CXCL11, are also expressed on/from nonimmune cells, including skin keratinocytes and fibroblasts (reviewed in [5]).…”

The Role of CXCR3 and Associated Chemokines in the Development of Atherosclerosis and During Myocardial Infarction

“…It seems that CXCL9 and CXCL10 promote inflammation through inducing T cell polarization into Th1/Th17 cells, while CXCL11 drives the development of regulatory T cells (Treg) cells which play a role in restraining inflammation (22). Based on the above, CXCR3 may be hypothesized to play a dual role by mediating both proinflammatory and anti-inflammatory pathways.…”

“…Meanwhile, CXCL4 and CXCL11 promoted the differentiation of T cells into Treg1 cells, responsible for restraining the inflammatory response through IL-10, TGF-β and contact dependent pathways (22, 35, 36). Platelet surface expression of CXCR4 and CXCR7 receptors is elevated in acute coronary syndrome compared to stable angina.…”

Dual Roles for CXCL4 Chemokines and CXCR3 in Angiogenesis and Invasion of Pancreatic Cancer

“…þ T cells, and natural killer cells and exhibits tumor-promoting abilities (9). CXCR3-B, which differs from CXCR3-A by an amino terminal extension, is believed to mediate angiostatic activities (7).…”